The invention is in the field of orally active androgenic hormones, more specifically xcex9414 derivatives of 19-nortestosterone.
Testosterone derivatives are known. As a medicine testosterone itself, the natural male hormone, has many known drawbacks as far as methods of administration are concerned. It has a short-lasting activity, is insoluble in the usual pharmaceutically acceptable media, and is not very potent. The more potent dihydrotestosterone (5xcex1-reduced form of testosterone) is considered a health-risk, notably for the prostate.
A more potent androgen is 7xcex1-methyl-19-nortestosterone (MENT) disclosed in FR 4,521 M and U.S. Pat. No. 5,342,834. An important drawback of MENT, however, is its unfavourable kinetics which limits its use as an orally active androgen.
In the field of pharmaceutical preparations in general it is a common desire for a medicinal agent to be orally active. Oral dosage forms, e.g. solid dosage forms such as tablets and capsules, are among the most widely accepted forms of administration. In the field of androgens, a particular desire exists for the oral administration in connection with a utility such as male contraception. Since in the area of female contraception the word xe2x80x9cpillxe2x80x9d has almost become a synonym for reliable birth-control, it is evident that also in the case of male contraception oral activity is desired, so as to enable providing a male xe2x80x9cpill.xe2x80x9d
An androgen having a special position in the field, is the so-called xe2x80x9cSegaloff steroidxe2x80x9d which is a 19-nortestosterone derivative having, as in MENT, a 7xcex1-methyl group, and which has a double bond between carbon atoms 14 and 15 (xcex9414). This special position is due to the fact that it has long been recognized as the most potent oral androgen known. See, int.al. Avery et al, Steroids, 55, 59 (1990). The compound, together with its 7xcex1-H analogue, is also known from GB 1,341,601.
Despite having a special position in the field, the xe2x80x9cSegaloff steroidxe2x80x9d has not found practical use, which may be due to several drawbacks it has for cllincal utility. E.g., with 19-nortestosterones metabolic stability is an issue. Thus it is known from GB 1,341,601 that these compounds are prone to metabolic inactivation by hepatic 17xcex2-hydroxysteroid dehydrogenase. The classic solution to this problem, the introduction of an alkyl group in the 17xcex1 position is believed to be responsible for unsatisfactory results such as a limited activity.
Several, mostly very old publications can be mentioned which form the further background-art relating to groups of steroid compounds which include 19-nortestosterone derivatives. None of these references teaches orally active androgens.
Thus, in FR 1,432,561, published in 1966, 19-nortestosterones like MENT having an alkyl substituent at C-7 are employed as a starting material for hormonal agents having a double bond between carbon atoms 5 and 6. Alkyl groups other than methyl are not disclosed.
BE 861 224 concerns all possible esters of a wide variety of 17-hydroxysteroids. The disclosure, which dates from 1976, specifically teaches that certain esters are desired for prolonged activitv of the steroids. Among the large group of steroids disclosed are oestrogens, anti-oestrogens, androgens and anabolics. A great many possible substituents at various positions is given, among which are methyl and ethyl at C-7.
Chemical Abstracts 110: 95601y (1989) refers to a 17-hydroxy acetate of 7-allyl-19-nortestosterone as an intermediate in the synthesis of 7-allyloestradiol.
EP 159 739 teaches immunomodulating agents of the oestrane series, including particularly xcex944- and xcex945(10)-oestrene derivatives having an alkyl substituent in position 6 or 7. Said alkyl substituent typically is methyl.
DE 20 43 404 concerns 7xcex2-steroids which have anti-hormonal activities. The alkyl substituent mostly is methyl, but ethyl and propyl are disclosed as well. In the synthesis of 7xcex2-ethyl-19-nortestosterone, which is a compound according to the teaching of DE 20 43 404, the 7xcex1-isomer is formed as well. It is not taught to use this isomer for anything, and the teaching of this document does not distinguish the ethyl or propyl substituents from the methyl moiety.
As background art reference is further made to Solo et al, Steroids, 40, 603-614 (1990). Disclosed herein are various 7xcex1-alkyl derivatives of testosterone.
It is an object of the invention to provide orally active androgens which are an improvement as compared to the Segaloff steroid in that they are better suitable for clinical use, and particularly possess sufficient oral activity and metabolic stability.
According to the invention, compounds are provided satisfying the general formula I given below. 
wherein
R1 is O, (H,H), (H,OR), NOR, with R being hydrogen, (C1-6) alkyl, or (C1-6) acyl;
R2 is selected from the group consisting of (C2-4) alkyl, (C2-4) alkenyl, or (C2-4,) alkynyl, each optionally substituted by halogen; or
R2 is cyclopropyl, or cyclopropenyl, each optionally substituted by (C1-2) alkyl, or halogen;
R3 is hydrogen, (C1-2) alkyl, or ethenyl;
R4 is (C1-2) alkyl;
R5 is hydrogen, or (C1-15) acyl;
and the dotted lines indicate optional bonds.
The invention includes pharmaceutically acceptable salts or esters, prodrugs and precursors of the above steroids.
The term (C1-6) alkyl as used in the definition of formula I means a branched or unbranched alkyl group having 1-6 carbon atoms, like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Likewise, the term (C2-4) alkyl means a branched or unbranched alkyl group having 2-4 carbon atoms and the term (C1-2) alkyl means an alkyl group having 1-2 carbon atoms.
The term (C2-4) alkenyl means a branched or unbranched alkenyl group having at least one double bond and 2-4 carbon atoms. Preferred alkenyl groups have 2-3 carbon atoms, such as vinyl and propenyl.
The term (C2-4) alkynyl means a branched or unbranched alkynyl group having at least one triple bond and 2-4 carbon atoms. Preferred alkynyl groups have 2-3 carbon atoms, such as ethynyl and propynyl.
The term (C1-6) acyl means an acyl group derived from a carboxylic acid having 1-6 carbon atoms, like formyl, acetyl, propanoyl, butyryl, 2-methylpropanoyl, pentanoyl, pivaloyl, and hexanoyl. Likewise, the term (C1-5) acyl means an acyl group derived from a carboxylic acid having 1-15 carbon atoms. Also included within the definition of (C1-6) acyl or (C1-15) acyl are acyl groups derived from dicarboxylic acids, like hemi-maloyl, hemi-succinoyl, hemi-glutaroyl, and so on. Preferred is hemi-succinoyl.
The term halogen means fluorine, chlorine, bromine, or iodine. When halogen is a substituent at an alkyl group, Cl and F are preferred, F being most preferred.
It is understood that the 7xcex1-substituted xcex944-nandrolone derivatives of the invention have the natural configurations 5xcex1, 8xcex2, 9xcex1, 10xcex2, 13xcex2, and 17xcex2.
The 7xcex1-substituted xcex9414-nandrolone derivatives of this invention have the natural configurations 5xcex1, 8xcex2, 9xcex1, 10xcex2, 13xcex2 and 17xcex2, and may possess also one or more additional chiral carbon atoms. The compounds may therefore be obtained as a pure diastereomer, or as a mixture of diastereomers. Methods for obtaining the pure diastereomers are well known in the art, e.g. crystallization or chromatography.
The compounds of the invention, which are distinguished from the aforementioned known xe2x80x9cSegaloff steroidxe2x80x9d by the length of the 7xcex1 substituent, surprisingly are an improvement over said known steroid and have unexpected advantages for clinical utility. This is exhibited by, inter alia, a surprisingly better oral activity. Preferred compounds of the invention further display a much better metabolic stability than the Segaloff steroid.
Preferred compounds of the invention have R2 selected from the group consisting of ethyl, ethenyl, ethynyl, propyl, 1-propenyl, 2-propenyl, 1-propynyl, 1,2-propadienyl, and cyclopropyl.
Even more preferred are compounds in which R1 is oxo, R3 is hydrogen, R4 is methyl, and the dotted lines indicate a xcex944 double bond.
Most preferred are those compounds in which R2 is C2, with the highest preference being ethyl or ethenyl.
The compounds of the invention may be produced by various methods known in the art of organic chemistry in general, and especially in the art of the chemistry of steroids (see, for example: Fried, J. et al, Organic Reactions in Steroid Chemistry, Volumes I and II, Van Nostrand Reinhold Company, New York, 1972).
Essential is the introduction of a saturated or unsaturated 7xcex1-substituent (optionally substituted by halogen) onto the steroid nucleus, and the introduction of a xcex9414 double bond. A convenient starting material for the preparation of compounds of formula I wherein R1 is oxo, R2, R3 and R4 have the previously given meaning, R5 is hydrogen, and the dotted lines indicate a xcex944 double bond, is for instance a gon-4-en-3-one derivative of general formula II, wherein R3 and R4 have the previously given meaning, and R6 is oxo, (17xcex1-H,17xcex2-OR7), or (17xcex1xe2x80x94Cxe2x89xa1CH,17xcex2xe2x80x94OR7), in which R7 is a hydroxy protecting group, such as an acyl group, like an acetyl group, a benzoyl group or a pivaloyl group, an alkoxyalkyl group, like an ethoxyethyl group or a tetrahydropyranyl (THP) group, or a silyl group, such as a trimethylsilyl group or a tert-butyldimethylsilyl group, whose synthesis is known in literature, or which can be prepared using standard methods. 
A possible synthesis route is as follows. A gon-4-en-3-one derivative of formula II can be converted to the the corresponding gona-4,6-dien-3-one derivative by using standard methods, e.g. by conversion to the 3-acyloxy- or 3-alkoxygona-3,5-diene derivative followed by reaction with 2,3,5,6-tetrachloro-1,4-benzoquinone [Solyom, S. et al, Steroids 35, 361 (1980)]. Then, the 7xcex1-substituent, or a precursor thereof, is introduced by conjugate addition (1,6-addition). For this reaction several methodologies are known in the art, among others:
1)-Conjugate addition of organocopper reagents [for conjugate additions of organocopper reagents, see Lipshutz, B. H. et al in Org. Reactions 41, p. 135, Wiley, New York, 1992].
2)-Transition metal-mediated (TiCl4, AlCl3, ZrCl4, etc.) reaction of an organosilicon compound [fonnal 1,6-addition; see e.g. Nickisch, K. et al, Tetrahedron Lett. 29, 1533 (1988)].
3)-Base-catalyzed conjugate addition of a dialkyl malonate, 2,2-dimethyl-1,3-dioxane-4,6-dione, or an alkyl cyanoacetate [see e.g. Cruz, R. et al, Austr. J. Chem. 35, 451 (1982)].
4)-Conjugate addition of a suitable cyanide (MCxe2x89xa1N, M is Li, Na, K, AlR2, SiR3 etc.).
In general, these methods result in the predominant or exclusive formation of the 7xcex1-isomer.
The 7xcex1-substituted gon-4-en-3-one thus obtained can be aromatized to the 3-hydroxygona-1,3,5(10)-triene [Yuan, S.-S. et al, Steroids 39, 279 (1982)] which then can be methylated to the 3-methoxy derivative. Conversion to a 3-methoxygona-1,3,5(10)-triene can also be achieved directly [Brito, M. et al, Synth. Commun. 26, 623 (1996)]. When R6 is (17xcex1-H,17xcex2-OR7), the 17-hydroxy group is deprotected and oxidized to produce a 3-methoxygona-1,3,5(10)-trien-17-one derivative [for oxidation reactions, see: Hudlicky, M., Oxidations in Organic Chemistry, ACS Monograph 186, Wash., DC, 1990]. When R6 is (17xcex1-Cxe2x89xa1-CH,17xcex2-OR7), the 17-hydroxy group is again deprotected and the 17xcex1-ethynyl-17xcex2-hydroxy derivative is converted to the 17-ketone e.g. by reaction with silver carbonate on celite [Rao, P. N. et al, Steroids 59, 621 (1994)] or other methods known in the art. In both cases, conversion to the 17-ketone can also be accomplished prior to aromatization.
The 3-methoxygona-1,3,5(10)-trien-17-one derivative thus obtained can be brominated directly, for instance by reaction with copper(II) bromide in benzene/methanol [Segaloff, A. et al, Steroids 22, 99 (1973)]. The 3-methoxygona-1,3,5(10)-trien-17-one derivative can also be converted to the enol acetate and then treated with bromine [Johnson, W. S. et al, J. Am. Chem. Soc. 79, 2005 (1957)], or to the enol silyl ether followed by reaction with e.g. N-bromosuccinimide [Heathcock, C. H. et al, J. Amer. Chem. Soc. 104, 6081 (1982)]. Dehydrobromination of the 16xcex1-bromoketone, e.g. by reaction with LiBr/Li2CO3/DMF [Bull, J. R. et al, J. Chem. Soc., Perkin Trans. I, 241 (1990)], usually results in a mixture of (14xcex2)-3-methoxygona-1,3,5(10),15-tetraen- 17-one and 3-methoxygona-1,3,5(10),14-tetraen-17-one derivatives. They can be separated whereafter the latter is reduced to the corresponding (17xcex2)-3-methoxygona-1,3,5(10),14-tetraen-17-ol derivative by use of sodium borohydride, lithium aluminium hydride or other reducing agents.
The 7xcex1-substituted 3-methoxygona-1,3,5(10)-trien-17-one derivative can also be converted to the corresponding cyclic 1,2-ethanediyl acetal which is then brominated to afford a (16xcex1)-16-bromo-3-methoxygona-1,3,5(10)-trien-17-one cyclic 1,2-ethanediyl acetal derivative. Bromination can be accomplished using pyridinium tribromide, phenyltrimethylammonium tribromide or other brominating agents known in the art [Rasmusson, G. H. et al, Steroids 22, 107 (1973)]. The 16xcex1-bromo compound is dehydrobrorinated by reaction with a base, e.g. potassium tert-butoxide in xylene or dimethyl sulfoxide, to give the xcex945 compound [Johnson, supra; Poirier, D. et al, Tetrahedron 47, 7751 (1991)]. Mild hydrolysis of the ethylene ketal, for instance by treatment with p-toluenesulfonic acid in a mixture of acetone and water [Johnson, supra], results in a 3-methoxygona-1,3,5(10),15-tetraen-17-one derivative which is then converted to a 3-methoxygona-1,3,5(10),14,16-pentaen-17-ol acetate by acid-catalyzed reaction with acetic anhydride, isopropenyl acetate or other acetylating agents [Rasmusson, supra; Bull, supra]. The acetate is treated with sodium borohydride or other reducing agents [Rasmusson, supra] to result in the formation of a (17xcex2)-3-methoxygona-1,3,5(10),14-tetraen-17-ol derivative. Optionally, a 3 -methoxygona-1,3,5(10),15-tetraen-17-one cyclic 1,2-ethanediyl acetal can be converted by acid-catalyzed isomerization into the corresponding xcex9414 derivative [Ponsold, K. et al, J. Prakt. Chem. 323, 819 (1981)]. Removal of the acetal and reduction of 17-oxo produces the (17xcex2)-3-methoxygona-1,3,5(10),14-tetraen-17ol derivative. A 3-methoxygona-1,3,5(10),15-tetraen-17-one can also undergo isomerization to give a mixture of (14xcex2)-3-methoxygona-1,3,5(10),15-tetraen-17-one and 3-methoxygona-1,3,5(10),14-tetraen-17-one derivatives which can be processed as described above.
Additional methods to introduce a xcex9415 double bond include: conversion of a 3-methoxygona-1,3,5(10)-trien-17-one derivative to the enol acetate and reaction with a palladium(II) salt [Takahashi, T. et al, Tetrahedron 41, 5747 (1985)], or reaction of the enolate with methyl 2-pyridinesulfinate [Dionne, P. et al, Steroids 62, 674 (1997)].
Birch reduction of the 7xcex1-substituted (17xcex2)-3-methoxygona-1,3,5(10),14-tetraen-17-ol derivative thus obtained [Caine, D. in Org. Reactions 23, p. 1, Wiley, New York, 1976] and hydrolysis of the resulting (17xcex2)-3-methoxygona-2,5(10),14-trien-17-ol derivative then provides a 7xcex1-substituted (17xcex2)-17-hydroxygona-4,14-dien-3-one derivative of the invention. In cases where the 7xcex1-substituent is constructed from a precursor thereof (i.e. an unsaturated 7xcex1-substituent, a malonic ester fragment, or a cyano group, see above), this operation, which can be accomplished using standard methods, often must take place simultaneously with the introduction of the xcex9414 double bond. The precise sequence of reaction steps needed for construction of the 7xcex1-substituent and for the introduction of the xcex9414 double bond, including the Birch reduction and the conversion of the resulting gona-2,5(10)-diene to the 7xcex1-substituted (17xcex2)-17-hydroxygona-4,14-dien-3-one derivative of the invention is dictated by methods common in synthetic strategy (see Example 4 and 5).
Compounds of the invention in which R1 is (H,H), (H,OR), NOR, with R being hydrogen, (C1-6) alkyl, (C1-6) acyl, are obtained, by using methods known in the art, from compounds of formula I in which R1 is oxo.
Compounds of the invention in which R5 is (C1-15) acyl are obtained, by using methods known in the art, from compounds of formula I in which R5 is hydrogen.
Compounds of the invention in which the dotted lines indicate a xcex945(10) double bond are produced from the xcex942.5(10) dienes obtained after the Birch reduction. Alternatively, they can be prepared from xcex944 derivatives by isomerization. 5xcex1-Reduced compounds of the invention are produced from xcex944 derivatives.
The invention will be further explained hereinafter with reference to the following Examples.